Objective: To investigate functional and structural connectivity in a randomised waiting group controlled exercise trial over three months.

Methods: 57 patients with relapsing-remitting MS (RRMS, 69% female, mean age 39 y, median EDSS 1.5) were 1:1 randomised to a waitlist control group (n=27) or a supervised and individualised aerobic exercise program (n=30, median number of ergometer sessions: 22 up to 1 hour). MRI was performed at baseline and after 3 months. Functional networks were reconstructed based on wavelet correlations from the BOLD time series and mean fractional anisotropy of tracks derived from probabilistic tractography for structural networks was used. These individual connectomes with 160 nodes based on the Destrieux atlas were analysed with graph theory on a global and nodal level. To analyse the topological reorganisation we adapted the hub disruption index with means of nodes' metrics per group. Cross-sectional data from 30 matched healthy controls (HC) served as a reference to elucidate the directions of network changes. We used ANOVA and linear mixed effects models to investigate group x time interactions.

Results: At baseline, both groups showed an increased functional connectivity compared to HC, while structural connectivity was lower. Both effects were pronounced in highly connected hub regions as indicated by the degree of nodes. After 3 months, the waiting group showed a decrease in functional connectivity (p=0.018) pronounced in hubs, while functional connectivity increased in the exercise group globally(p=0.002). We observed a similar effect in structural connectomes: The waiting group remained unchanged after 3 months and the exercise group showed a globally increased structural connectivity (p=0.002). Moreover, we observed an increased clustering i.e. higher local connectivity in the exercise group within 3 months (p< 0.001), again predominantly in hub regions.

Conclusion: An aerobic exercise intervention increases functional and structural connectivity in RRMS after three months. The effect seems to be pronounced on a local level in hub regions.